Carboxyl-terminal proteolytic processing of matrix Gla protein.
Carboxyl-terminal proteolytic processing of matrix Gla protein.
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DOI：
10.1016/s0021-9258(18)54832-8
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发表时间：
1991-11
期刊：
影响因子：
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通讯作者：
J. Hale;M. Williamson;Paul A. Price
中科院分区：
文献类型：
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作者：
J. Hale;M. Williamson;Paul A. Price
本研究进行，以确定在基质Gla蛋白（MGP），10 kDa的蛋白质，其中含有5个残基的维生素K依赖性钙离子结合氨基酸，γ-羧基谷氨酸（Gla）的COOH-末端蛋白水解加工的程度。从牛皮质骨的脱矿和尿素提取物中分离出两种形式的MGP，一种长度为79个残基，COOH末端为Phe-Arg-Gln，另一种长度为83个残基，COOH末端为Phe-Arg-Gln-Arg-Arg-Gly-Ala。从信息结构预测的牛MGP的84-残基形式在骨细胞外基质提取物中不能检测到，因此似乎可能在分泌前通过羧肽酶B样酶的作用除去了位置84的赖氨酸。能够产生79个残基形式的MGP的蛋白水解裂解的合理序列是在Arg 80-Arg 81或Arg 81-Gly 82处的胰蛋白酶样裂解，随后是羧肽酶B样裂解以除去COOH末端精氨酸。由于在牛关节软骨和血浆中也检测到基本上等量的79-和83-残基形式的MGP，因此在骨中鉴定的COOH-末端加工事件似乎适用于合成该蛋白的许多其他组织。在人骨提取物中仅检测到一种形式的MGP，其为缺少COOH末端残基Arg-Lys-Arg-Arg-Gly-Thr-Lys的77个残基的蛋白质。这种人MGP的缩短形式与所提出的COOH末端加工模型一致，因为人蛋白质COOH末端的氨基酸取代，Lys 79取代Gln 79，将允许通过羧肽酶B样酶活性的作用从人MGP COOH末端去除额外的碱性残基。最近的研究表明，在成纤维细胞、软骨细胞和成骨细胞中，视黄酸强烈诱导MGP，这一反应表明MGP介导视黄酸对细胞生长或分化的作用。如果这一假设是真的，目前的证据复杂的COOH-末端加工事件可以提供一种手段来调节尚未未知的活性MGP在细胞外环境中的机制类似于激素，如anaphlotoxins和激肽的激活。
The present study was undertaken to determine the extent of COOH-terminal proteolytic processing in matrix Gla protein (MGP), a 10-kDa protein which contains 5 residues of the vitamin K-dependent Ca2+ binding amino acid, gamma-carboxyglutamic acid (Gla). Two forms of MGP were isolated from demineralization and urea extracts of bovine cortical bone, one 79 residues in length with the COOH terminus Phe-Arg-Gln and the other 83 residues in length with the COOH terminus Phe-Arg-Gln-Arg-Arg-Gly-Ala. The 84-residue form of bovine MGP predicted from the message structure could not be detected in the bone extracellular matrix extracts, and it therefore seems probable that the lysine at position 84 was removed by the action of a carboxypeptidase B-like enzyme prior to secretion. A plausible sequence of proteolytic cleavages that could generate the 79-residue form of MGP would be a trypsin-like cleavage at Arg80-Arg81 or Arg81-Gly82 followed by carboxypeptidase B-like cleavage to remove COOH-terminal arginine(s). Since essentially equal amounts of the 79- and 83-residue forms of MGP were also detected in bovine articular cartilage and plasma, it seems likely that the COOH-terminal processing events identified in bone apply to many of the other tissues which synthesize this protein. Only one form of MGP was detected in human bone extracts, a 77-residue protein that lacks the COOH-terminal residues Arg-Lys-Arg-Arg-Gly-Thr-Lys. This shortened version of human MGP is consistent with the proposed model for COOH-terminal processing, since the amino acid substitution in the COOH terminus of the human protein, Lys79 for Gln79, would allow removal of the additional basic residues from the human MGP COOH terminus by the action of the carboxypeptidase B-like enzymic activity. Recent studies have shown that MGP is strongly induced by retinoic acid in fibroblasts, chondrocytes, and osteoblasts, a response which suggests that MGP mediates an action of retinoic acid on an aspect of cell growth or differentiation. If this hypothesis is true, the present evidence for complex COOH-terminal processing events could provide a means to regulate the as yet unknown activity of MGP in the extracellular environment in a mechanism similar to the activation of hormones such as anaphlotoxins and kinins.